Modulation of OPRM1 Alternative Splicing by Morphine and HIV-1 Nef.
Modulation of OPRM1 Alternative Splicing by Morphine and HIV-1 Nef.
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DOI：
10.1007/s11481-021-10009-4
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发表时间：
2022-06
期刊：
影响因子：
--
通讯作者：
Sariyer IK
中科院分区：
文献类型：
--
作者：
Donadoni M;Huang W;Yarandi SS;Burdo TH;Chang SL;Sariyer IK
临床上使用的阿片样物质，例如吗啡，激活由阿片样物质受体Mu 1（OPRM 1）基因编码的μ阿片样物质受体（莫尔）。阿片受体基因的检查表明，人OPRM 1前mRNA经历了广泛的选择性剪接事件，并能够表达21种亚型。然而，OPRM 1信号转导的表征是一般化的，并且只有一种同种型（莫尔-1）被广泛研究。使这一问题更加复杂的是静脉注射药物滥用在艾滋病毒神经发病机制中的重要性日益增加。在这里，我们研究了吗啡和HIV-1在体外和体内模型中对OPRM 1前mRNA切片调节的分子影响。我们的研究结果表明，吗啡治疗特异性诱导的选择性剪接的莫尔-1X异构体之间的其他异构体在神经元细胞中分析。有趣的是，莫尔-1X亚型的选择性剪接和表达也在从HIV感染者（PWH）获得的死后脑组织中诱导。此外，用吗啡处理对照大鼠诱导了与奖赏途径有关的脑区中莫尔-1 X的选择性剪接。更有趣的是，HIV-1转基因（HIV-1 Tg）大鼠在暴露于吗啡的情况下显示出莫尔-1X同种型的叠加诱导。为了进一步探讨HIV分泌蛋白在OPRM 1基因选择性剪接中的作用，我们分析了HIV-1达特、gp 120和Nef蛋白对莫尔-1X亚型选择性剪接的影响。虽然达特和gp 120没有明显的作用，但用Nef处理神经元诱导的莫尔-1X选择性剪接与用吗啡处理相当。总之，我们的研究结果表明，HIV-1可能通过放大吗啡诱导的莫尔-1X选择性剪接的速率来改变莫尔亚型与Nef蛋白的表达。
Clinically used opioids, such as morphine, activate the mu opioid receptor (MOR) encoded by Opioid Receptor Mu 1 (OPRM1) gene. Examination of the opioid receptor genes showed that the human OPRM1 pre-mRNA undergoes extensive alternative splicing events and capable of expressing 21 isoforms. However, characterization of OPRM1 signaling is generalized, and only one isoform (MOR-1) has been extensively studied. Compounding this issue is the increasing significance of intravenous drug abuse in HIV neuropathogenesis. Here, we investigated the molecular impact of morphine and HIV-1 on regulation of OPRM1 pre-mRNA slicing in in vitro and in vivo models. Our results suggested that morphine treatment specifically induces the alternative splicing of MOR-1X isoform among the other isoforms analyzed in neuronal cells. Interestingly, alternative splicing and expression of MOR-1X isoform was also induced in postmortem brain tissues obtained from people with HIV (PWH). Additionally, treatment of control rats with morphine induced alternative splicing of MOR-1X in the brain regions involved in the reward pathways. More interestingly, HIV-1 transgenic (HIV-1Tg) rats, showed an additive induction of MOR-1X isoform with the exposure to morphine. To further assess the possible role of HIV secretory proteins in alternative splicing of OPRM1 gene, we analyzed the impact of HIV-1 Tat, gp120 and Nef proteins on alternative splicing of MOR-1X isoform. While the Tat and gp120 had no visible effects, treatment of neurons with Nef induced MOR-1X alternative splicing that was comparable to treatment with morphine. Altogether, our results suggest that HIV-1 may alter MOR isoform expression with Nef protein by amplifying the rate of MOR-1X alternative splicing induced by morphine.
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影响因子：
3.3
作者：
Abbadie, C;Pasternak, GW;Aicher, SA
通讯作者：
Aicher, SA
影响因子：
1.7
作者：
Abbadie, C;Pasternak, GW
通讯作者：
Pasternak, GW
影响因子：
3.3
作者：
Gibellini, Davide;Alviano, Francesco;Re, Maria Carla
通讯作者：
Re, Maria Carla
影响因子：
11.2
作者：
BREW, BJ;ROSENBLUM, M;PRICE, RW
通讯作者：
PRICE, RW
DOI：
10.1007/s11427-009-0037-0
发表时间：
2009-03-01
期刊：
SCIENCE IN CHINA SERIES C-LIFE SCIENCES
影响因子：
--
作者：
Hui JingYi
通讯作者：
Hui JingYi